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From obesity-associated steatosis to liver cancer: The role of transcriptional, post-translational, and immune response networks in disease progression

par Li, Ao
Président du jury Remmelink, Myriam
Promoteur Gurzov, Esteban Nicolas
Publication Non publié, 2026-02-05

Thèse de doctorat

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Résumé :

The progression from hepatic steatosis to hepatocellular carcinoma (HCC) in obesity results from multistep processes, including ectopic fat accumulation, metabolic stress, and inflammation. Dysregulated transcriptional networks, metabolic reprogramming, and inflammatory response amplify the dysfunction in the liver, leading to hepatocyte maladaptation and malignant transformation. It is shown that these signal transduction pathways are controlled by transcription factors, protein phosphatases, and lectins in the liver. However, the mechanisms regulated by c-Fos/AP-1 (transcription factor), PTPRK (protein tyrosine phosphatase), and galectin-1 (lectin) that disrupt hepatocyte metabolism during different stages of metabolic liver disease remain unknown. Here, we provide a comprehensive study of c-Fos, protein tyrosine phosphatase receptor type K (PTPRK), and galectin-1 during liver disease progression in obesity.In the first chapter of my PhD, we assessed the role of the transcription factor c-Fos in regulating transcriptional networks in metabolic liver disease. To assess the function of c-Fos in hepatocytes, we applied advanced methods to analyse public RNA sequencing datasets of primary mouse hepatocytes, mouse models with adenovirus-manipulated c-Fos expression or obesogenic diets, as well as human stem cells and hepatoma cells. We demonstrated that c-Fos expression is dynamically induced by insulin and nutrients and elevated in hepatocytes under metabolic stress. Persistent expression of c-Fos creates an abnormal transcriptional pattern, which boosts glycolysis and stimulates lipogenesis through PPAR signalling, thus leading to harmful lipid accumulation and metabolic stress that can contribute to HCC development.In the second and third chapters of this study, we focused on metabolic regulation at the protein level. We found that PTPRK is elevated in human and murine steatotic livers. We used both global and hepatocyte-specific knockout mouse models, primary mouse hepatocytes, human stem cells, and hepatoma cells to assess the role of PTPRK in metabolic liver disease. We showed that PTPRK knockout in both global and liver-specific mouse models resulted in protection against diet-induced obesity, steatosis, and liver carcinogenesis, with suggested mechanisms of regulating glycolysis and lipogenesis via the PTPRK-FBP1-PPARγ axis.Finally, we investigated inflammatory regulators in metabolic liver disease. We discovered that metabolic liver disease progression leads to increased hepatic galectin-1, which could result from inflammatory responses and hypoxic conditions. Our in vivo neutralising antibody in mouse study and single-nuclei RNA sequencing analysis revealed that blocking galectin-1 affects disease-related hepatocytes subpopulations and plasticity and modifies lipid-associated macrophage maturation at the transcriptional level during diet-induced steatohepatitis.Overall, this study demonstrates the pivotal role of hepatocyte c-Fos and PTPRK in glycolysis and fat accumulation in the liver, which leads to metabolic reprogramming in metabolic liver disease and HCC. Moreover, our results show that galectin-1 acts as an inflammatory protein, and anti-galectin-1 blocking antibodies pose therapeutic potential for treating steatohepatitis.